Recent work by Osselaere and Lapiere showed that some derivatives of 4-oxo-3,4-dihyropyrido[2,3d]pyrimidine had diuretic activity. (Eur. J. Med. Chem., 9:310 (1974); Eur. J. Med. Chem., 9:305 (1974)). They examined a series consisting of pyridyl and substituted phenyl groups attached at the 2 position on the pyrimidine ring. The most effective was 4-oxo-2-(3-pyridyl)-3,4-dihydropyrido[2,3d]pyrimidine (I, R=3-pyridyl). ##STR5## Osselaere and Lapiere, however, did not examine heterocyclic derivatives other than the pyridyl group.
Many investigators have studied the relationship between structure and diuretic activity for the many known diuretic compounds. See, for example, the work of Jackman, et al., J. Pharm. Pharmacol., 14:679 (1962); Siedel, et al., Chem. Ber., 99:328 (1966); Sturm, et al., Chem. Ber., 99:328 (1966); Feit, et al., J. Med. Chem. 13:1071 (1970) and Feit, et al., J. Med. Chem., 17:572 (1974), and in particular the discussions of furosemide, one of the most successful diuretics, and other aryl sulfonamides. It appears that the furyl moiety of these aryl sulfonamide compounds is important for diuretic activity. Other diuretic compounds somewhat related structurally to furosemide also have a furyl moiety. See, for example, U.S. Pat. Nos. 3,001,994; 3,058,882; 3,163,644; 3,839,321; and 4,064,239.
It is further known that chlorothiazide (II), a known diuretic, may be modified by reduction of the 1,2 double bond in the heterocyclic ring to form hydrochlorothiazide (III), having increased diuretic activity. (Osol, Ed., Remington's Pharmaceutical Science, 15th Ed., Mack Publ. Co., Easton, Pa., (1975), p. 868). ##STR6##
The present invention is an extension of this structure-activity work in that it combines teachings from various divergent areas of the diuretic art to arrive at novel compounds having exellent diuretic activity without causing potassium ion depletion and having low toxicity.
East German Pat. No. 73039 (Kretzschmar, et al.) discloses compounds of the formula: ##STR7## wherein R.sub.1 is hydrogen or lower alkyl having 1-5 carbon atoms (straight or branched) and R.sub.2 is lower alkyl having 1-5 carbon atoms (straight or branched) or aralkyl, aralkylidene or aryl, wherein the ring may be substituted with halogen, alkoxy, hydroxy, nitro, or tertiary amino. The compounds are disclosed as antitumor agents.